Analgetic composition and method employing 1-morpholinomethyl-5-ethyl-5-phenyl babituric acid

ABSTRACT

The use of 1-morpholinomethyl-5-ethyl-5-phenyl barbituric acid as an analgetic agent is described.

United States Patent Vida [54] ANALGETIC COMPOSITION AND METHOD EMPLOYING 1- MORPHOLlNOMETHYL-S-ETHYL-S- PHENYL BABITURIC ACID [72] Inventor: Julius A. Vida, Boston, Mass.

[73] Assignee: The Kendall Company, Walpole,

Mass.

22 Filed: Nov. 9, 1970 21 Appl.No.: 88,195

[52] US. Cl. ..424/248 [51] Int. Cl. ..A6lk 27/00 [451 Aug. 8, 1972 Chem. Abst. 68 105144g (1968) Primary Examiner-Stanley J. Friedman A!t0rneyEllen P. Trevors and Robert D. Chodera [5 7] ABSTRACT The use of 1-morpholinomethyl-S-ethyl-S-phenyl barbituric acid as an analgetic agent is described.

2 Claims, No Drawings ANALGETIC COMPOSITION AND METHOD EMPLOYING l-MORPHOLINOMETHYL-S- ETHYL-S-PI'IENYL BABITURIC ACID This invention relates to the use of morpholinomethyl--ethyl-5-phenyl barbituric acid as an analgetic for treating symptoms of pain in warmblooded animals, and to therapeutic compositions containing this compound.

l-Morpholinomethyl-5-ethyl-5-phenyl barbituric acid has been previously reported in the literature. Thus, L. Rylski et al., Acta Pol. Pharm. 24 (4): 366-70 (1967) disclose the preparation of this compound, but do not indicate specific therapeutic uses therefor.

Now it has been found in accordance with this invention that l-morpholinomethyl-S-ethyl-S-phenyl barbituric acid is an effective analgetic agent for alleviating symptoms of pain in warm-blooded animals.

This compound is readily provided by reacting 5- ethyl-S-phenyl barbituric acid, which is generally referred to as phenobarbital, with morpholine, hydrochloric acid and formaldehyde, or aqueous solutions of formaldehyde, as described in the aforementioned L. Rylski et al. reference.

The analgetic of this invention can be formulated with conventional physiologically acceptable vehicles and carriers to make syrups, isotonic solutions, tablets and other dosage forms. Effectiveness and toxicity of this compound is such that each dosage unit can contain from 5 to 500mg of active material.

All tests were conducted on adult albino male mice (Charges River strain); the dosage consisted of the active agent suspended in percent aqueous acacia and was administered orally unless otherwise indicated.

Acute oral toxicity and acute intraperitoneal toxicity were determined in the conventional manner. The results were expressed as LD the dose required to produce death in 50 percent of the animals treated, determined graphically, with the 95 percent limits shown in parentheses.

Two established procedures were employed to determine analgetic activity. The method described by Eddy, NH, and Leimbach, D., J. Pharmacol. Exptl. Therap. 107: 385 (1953) was followed, with the following modifications, in the first procedure. Mice are pretested by placing them individually on the cleaned surface of a copper water bath, the temperature of which is maintained at 5455 C. The reactiontime to this noxious thennal stimulus is the time in seconds required for either licking of the paws or jumping, such that all four paws leave the surface of the plate. The drug is then administered orally or subcutaneously,

' generally at 5 dosage levels, (10 mice per dosage level) or exceeding this cut-ofi time are considered to represent analgetic responses. The dosage required to produce an analgetic response in 50 percent of the animals (ED and 95 percent limits) is computed gr' ip cally. n e second procedure, the method of Slegmund, E., et. al. reported in Proc. Soc. Exptl. Biol. and Med. 95: 729, (1957) was generally followed. The method is based on the antagonism by both non-narcotic and narcotic analgetics of a syndrome induced in mice following intraperitoneal injection of phenylparaquinone. The syndrome is characterized by intermittent contractions of the abdomen, twisting and turning of the trunk, and extension of the hind legs, beginning 3 to 10 minutes after the injection and persisting for more than 1 hour. The test drug is administered orally at 4 to 5 dosage levels. At the time of peak activity, 0.25m] of a 0.02 percent solution of phenylparaquinone in 5 percent (aqueous) ethyl alcohol is injected intraperitoneally. Inhibition of the syndrome is considered an analgetic response. The dosage required for this effect in 50 percent of the mice (ED is computed graphically.

The following example will serve to illustrate the practice of this invention.

EXAMPLE Following the procedure disclosed by L. Rylski et al. in Acta Pol. Pharm. 24 (4): 36973 (1967), 23.0g. of 5-ethyl-5-phenyl barbituric acid was added to the solution of 8.7ml of morpholine and 8.0m] of 37 percent aqueous formaldehyde in 50ml absolute ethanol. After heating at reflux for 30 minutes, the reaction mixture was allowed to cool to room temperature, and then refrigerated overnight. Filtration, followed by washing with ethanol, provided 32g. of l-morpholinomethyl-S- ethyl-S-phenyl barbituric acid, m.p. 73 C.

Pharmacological testing of this compound gave the following results:

Dosage, mg/kg Acute Toxicity LD (oral) 250, 500 Analgetic Activity Hot-Plate ED (subcutaneous) 36(27. l-47.9) Hot-Plate ED (oral) 3.125

(A non-linear dosage response curve was obtained.) Phenyl-p-quinone Wn'thing 50 ED (oral) Time of Peak Activity l hour What 18 claimed 1s:

1. A method of treating symptoms of pain in a wannblooded animal which comprises administering to said animal an analgetically effective amount of lmorpholinomethyl-S-ethyl-5-phenyl barbituric acid.

2. A therapeutic composition for treatment of symptoms of pain in a warm-blooded animal comprising a physiologically acceptable carrier and an analgetically effective amount of l-morpholinomethyl-5-ethyl-5- phenyl barbituric acid. 

2. A therapeutic composition for treatment of symptoms of pain in a warm-blooded animal comprising a physiologically acceptable carrier and an analgetically effective amount of 1-morpholinomethyl-5-ethyl-5-phenyl barbituric acid. 